Disability in clinical neurology frequently results from axonal damage rather than neuronal cell loss. Spinal cord injury is an example where successful axonal regeneration holds the potential for extensive functional recovery. Recent work has uncovered a number of the molecular determinants of axonal regeneration. The CMS myelin proteins, Nogo-A, MAG and OMgp, inhibit axonal growth in tissue culture. All three proteins bind to one axonal receptor, the Nogo-66 receptor (NgR), to initiate a signaling cascade that inhibits axonal extension. Reactive astrocytes secrete chondroitin sulfate proteoglycans (CSPGs) that also limit axonal growth, especially near injury sites. The growth of adult axons is dependent on cell autonomous positive factors as well as the presence of extracellular inhibitory proteins. Peripheral axotomy successfully induces a regeneration gene program, while central axotomy of the same neuron has much less effect. Proteins that are induced selectively after peripheral axotomy but not central axotomy include GAP-43, SPRRIA and Fn14. This project seeks to examine the role of myelin inhibitors and CSPGs in CMS axonal regeneration using genetic and molecular means, with spinal cord injury as a model. The role of SPRR1A and Fn14 in peripheral nerve regeneration will also be assessed genetically, and their mechanism of axon growth enhancement will be probed. Together, these aims seek to advance our molecular understanding of the extrinsic and intrinsic factors that determine the success of axonal regeneration, and have the potential to provide new therapeutic modalities to improve nervous system function after a wide range of chronic neurologic injuries.